Search

US-20260124177-A1 - CO-THERAPIES INCLUDING A METASTASIS INHIBITOR

US20260124177A1US 20260124177 A1US20260124177 A1US 20260124177A1US-20260124177-A1

Abstract

Provided are methods of increasing a response to a chemotherapeutic agent or an immunotherapeutic agent in a patient in need thereof, and methods of treating cancer in a patient in need thereof, comprising administering to the patient a chemotherapeutic agent or an immunotherapeutic agent and a metastasis inhibiting compound, as described in this disclosure.

Inventors

  • XIN-YUN HUANG
  • Jue Jillian ZHANG
  • Christy Young Shue

Assignees

  • NOVITA PHARMACEUTICALS, INC.
  • CORNELL UNIVERSITY

Dates

Publication Date
20260507
Application Date
20251230

Claims (20)

  1. 1 . A method of increasing a response to a chemotherapeutic agent or an immunotherapeutic agent in a patient in need thereof, comprising: administering to the patient a compound represented by formula (I): or tautomer thereof, and/or a pharmaceutically acceptable salt thereof, wherein R 2 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 R 4 , wherein each R 4 is independently selected from the group consisting of lower alkyl, lower haloalkyl, —OH, —OR 7 , —SH, —SR 7 , —NR 10 R 10 , halo, cyano, nitro, —COH, —COR 7 , —CO 2 H, —CO 2 R 7 , —CONR 10 R 10 , —OCOR 7 , —OCO 2 R 7 , —OCONR 10 R 10 , —NR 10 COR 10 , —NR 10 CO 2 R 10 , —SOR 7 , —SO 2 R 7 , SO 2 NR 10 R 10 , phenyl (optionally substituted with lower alkyl, halo or lower haloalkyl, or —OH), and —NR 10 SO 2 R 7 ; each R 3 is independently selected from the group consisting of lower alkyl, lower haloalkyl, —OH, —OR 7 , —SH, —SR 7 , —NR 10 R 10 , halo, cyano, nitro, —COH, —COR 7 , —CO 2 H, —CO 2 R 7 , —CONR 10 R 10 , —OCOR 7 , —OCO 2 R 7 , —OCONR 10 R 10 , —NR 10 COR 10 , —NR 10 C 2 O 2 R 10 , —SOR 7 , —SO 2 R 7 , SO 2 NR 10 R 10 , and —NR 10 SO 2 R 7 ; m is 0, 1, 2 or 3; R 7 is lower alkyl; and each R 10 is independently hydrogen or lower alkyl, or two R 10 together with the atom(s) attached thereto form a 4- to 6-membered ring; Y is selected from the group consisting of CF 3 , Cl, F and Me, wherein the patient is undergoing or about to undergo chemotherapy or immunotherapy.
  2. 2 . The method of claim 1 , wherein the patient is undergoing or about to undergo immunotherapy.
  3. 3 . The method of claim 2 , wherein the immunotherapy is selected from an immune checkpoint inhibitors such as anti-PD-1 antibody or anti-CTLA-4 antibody.
  4. 4 . The method of claim 1 , wherein the patient is undergoing or about to undergo chemotherapy.
  5. 5 . The method of claim 4 , wherein the chemotherapy is selected from paclitaxel, cyclophosphamide, or doxorubicin.
  6. 6 . The method of claim 1 , wherein the compound represented by formula (I) and a chemotherapeutic agent or an immunotherapeutic agent are administered within one year of one another.
  7. 7 . The method of claim 1 , wherein the compound represented by formula (I) and a chemotherapeutic agent or an immunotherapeutic agent are administered within one month of one another.
  8. 8 . The method of claim 1 , wherein the compound represented by formula (I) and a chemotherapeutic agent or an immunotherapeutic agent are co-administered.
  9. 9 . The method of claim 1 , wherein the patient suffers from cancer.
  10. 10 . The method of claim 9 , wherein the cancer is selected from group consisting of a carcinoma, lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma, colon carcinoma, pancreatic carcinoma, esophageal carcinoma, stomach carcinoma, urinary carcinoma, bladder carcinoma, breast cancer, gastric cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, renal cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampulla cancer, biliary duct cancer, and larynx cancer.
  11. 11 . The method of claim 1 , wherein, in the compound of Formula I, R 2 is 5- or 6-membered heteroaryl optionally substituted with 1 to 4 R 4 .
  12. 12 . The method of claim 11 , wherein, in the compound of Formula I, R 2 is optionally substituted with 1 to 4 R 4 , and R 2 is selected from the group consisting of furan, benzofuran, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, imidazole, pyrrole, and pyrazole.
  13. 13 . The method of claim 11 , wherein, in the compound of Formula I, R 2 is selected from the group consisting of
  14. 14 . The method of claim 11 , wherein, in the compound of Formula I, R 4 is not optional and is selected from the group consisting of lower alkyl, halo, lower haloalkyl, —OH, —OR 7 , cyano and phenyl optionally substituted methyl, and wherein R 7 is lower alkyl or lower haloalkyl.
  15. 15 . The method of claim 11 , wherein, in the compound of Formula I, m is 0.
  16. 16 . The method of claim 11 wherein, the compound of Formula I is selected from: or tautomer thereof, and/or a pharmaceutically acceptable salt thereof.
  17. 17 . The method of claim 11 , wherein the patient is an adult human.
  18. 18 . A method of treating cancer in a patient in need thereof, comprising administering to the patient a chemotherapeutic agent or an immunotherapeutic agent and a compound represented by formula (I): or tautomer thereof, and/or a pharmaceutically acceptable salt thereof, wherein R 2 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 R 4 , wherein each R 4 is independently selected from the group consisting of lower alkyl, lower haloalkyl, —OH, —OR 7 , —SH, —SR 7 , —NR 10 R 10 , halo, cyano, nitro, —COH, —COR 7 , —CO 2 H, —CO 2 R 7 , —CONR 10 R 10 , —OCOR 7 , —OCO 2 R 7 , —OCONR 10 R 10 , —NR 10 COR 10 , —NR 10 CO 2 R 10 , —SOR 7 , —SO 2 R 7 , SO 2 NR 10 R 10 , phenyl (optionally substituted with lower alkyl, halo or lower haloalkyl, or —OH), and —NR 10 SO 2 R 7 ; each R 3 is independently selected from the group consisting of lower alkyl, lower haloalkyl, —OH, —OR 7 , —SH, —SR 7 , —NR 10 R 10 , halo, cyano, nitro, —COH, —COR 7 , —CO 2 H, —CO 2 R 7 , —CONR 10 R 10 , —OCOR 7 , —OCO 2 R 7 , —OCONR 10 R 10 , —NR 10 COR 10 , —NR 10 C 2 O 2 R 10 , —SOR 7 , —SO 2 R 7 , SO 2 NR 10 R 10 , and —NR 10 SO 2 R 7 ; m is 0, 1, 2 or 3; R 7 is lower alkyl; and each R 10 is independently hydrogen or lower alkyl, or two R 10 together with the atom(s) attached thereto form a 4- to 6-membered ring; Y is selected from the group consisting of CF 3 , Cl, F and Me.
  19. 19 . The method of claim 18 , wherein the patient is undergoing or about to undergo immunotherapy.
  20. 20 . The method of claim 18 , wherein the patient is undergoing or about to undergo chemotherapy.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a Continuation of U.S. application Ser. No. 18/201,079, filed on May 23, 2023, which is a Continuation of U.S. Non-Provisional application Ser. No. 16/766,156, filed on May 21, 2020, which is the U.S. National Stage of PCT/US2018/062069, filed Nov. 20, 2018, which claims priority to U.S. Provisional Application No. 62/590,067, filed on Nov. 22, 2017, the contents of each of which are incorporated herein by reference. FIELD The present technology relates generally to compounds, compositions and methods for treating or preventing cancer. BACKGROUND Tumor metastasis is the major cause of mortality of cancer patients. Inhibition of tumor metastasis will significantly increase the survival rate of cancer patients. Metastasis is a multi-step process wherein a primary tumor spreads from its initial site to secondary tissues/organs. Weiss, L. Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev 19, I-XI, 193-383 (2000); Fidler, I. J. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3, 453-458 (2003); Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275-292, (2011). Tumor cell migration and organ invasion are critical steps in metastasis. Condeelis, J., Singer, R. H. & Segall, J. E. The great escape: when cancer cells hijack the genes for chemotaxis and motility. Annu Rev Cell Dev Biol 21, 695-718 (2005). Migration provides tumor cells the ability to leave the primary tumor bed (local invasion), enter into blood vessels, and then exit the circulation and infiltrate distant tissues/organs. There have been important new insights into the biology of local tumor growth, and these are being exploited as new targets for treatment. But it is critical also to understand and interrupt the process of tumor metastasis as that is ultimately the terminal event leading to cancer mortality. For cell migration and invasion to proceed, actin cytoskeleton must be reorganized by forming polymers and bundles to cause dynamic changes in cell shapes. Id.; Mogilner, A. & Rubinstein, B. The physics of filopodial protrusion. Biophys J 89, 782-795 (2005); Pollard, T. D. & Cooper, J. A. Actin, a central player in cell shape and movement. Science 326, 1208-1212, (2009). Among the morphological structures supported by actin filaments, one of the most prominent protrusive organelles is filopodia which are fundamental to cell shape and motility events. Mattila, P. K. & Lappalainen, P. Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol 9, 446-454, (2008). Filopodia are finger-like plasma membrane protrusions that are formed upon remodeling of the actin cytoskeleton beneath the plasma membrane. They can be viewed as a sensory organ of the cells that are used to detect and assimilate signals as well as to explore and move into the surrounding microenvironment. avenport, R. W., Dou, P., Rehder, V. & Kater, S. B. A sensory role for neuronal growth cone filopodia. Nature 361, 721-724, doi:10.1038/361721a0 (1993); Bentley, D. & Toroian-Raymond, A. Disoriented pathfinding by pioneer neurone growth cones deprived of filopodia by cytochalasin treatment. Nature 323, 712-715, doi:10.1038/323712a0 (1986); Sanders, T. A., Llagostera, E. & Barna, M. Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Nature 497, 628-632, doi:10.1038/nature12157 (2013). They contain long actin filaments crosslinked into parallel bundles by the fascin protein. Metastatic tumor cells are rich in filopodia, and the numbers of filopodia correlate with their invasiveness. Filopodia-like protrusions have also been shown to be critical for metastatic tumor cells to interact with the metastatic microenvironment and to grow at the secondary tissues. ue, T., Brooks, M. W., Inan, M. F., Reinhardt, F. & Weinberg, R. A. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer discovery 2, 706-721 (2012). Fascin is the main actin cross-linker in filopodia and shows no amino acid sequence homology with other actin-binding proteins. to, J. J., Kane, R. E. & Bryan, J. Formation of filopodia in coelomocytes: localization of fascin, a 58,000 dalton actin cross-linking protein. Cell 17, 285-293 (1979); Bryan, J. & Kane, R. E. Separation and interaction of the major components of sea urchin actin gel. J Mol Biol 125, 207-224 (1978); Yamashiro-Matsumura, S. & Matsumura, F. Purification and characterization of an F-actin-bundling 55-kilodalton protein from HeLa cells. J Biol Chem 260, 5087-5097 (1985); Vignjevic, D. et al. Formation of filopodia-like bundles in vitro from a dendritic network. J Cell Biol 160, 951-962 (2003); Vignjevic, D. et al. Role of fascin in filopodial protrusion. J Cell Biol 174, 863-875 (2006); Adams, J. C. Roles of fascin in cell adhesion and motility. Curr Op